A phase I, dose-finding study of sorafenib in combination with gemcitabine and radiation therapy in patients with unresectable pancreatic adenocarcinoma: a Grupo Español Multidisciplinario en Cáncer Digestivo (GEMCAD) study

Abstract

Purpose: Sorafenib, an oral inhibitor of B-raf, VEGFR2, and PDGFR2-beta, acts against pancreatic cancer in preclinical models. Due to the radio-sensitization activity of both sorafenib and gemcitabine, we designed a multicenter, phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy.

Methods: Patients with biopsy-proven, unresectable pancreatic adenocarcinoma (based on vascular invasion detected by computed tomography) were treated with gemcitabine (300 mg/m2 i.v. weekly ×5 weeks) concurrently with radiation therapy (45 Gy in 25 fractions) and sorafenib (escalated doses in a 3+3 design, from 200 to 800 mg/day). Radiation portals included the primary tumor but not the regional lymph nodes. Patients with planning target volumes (PTV) over 500 cc were excluded. Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression.

Results: Twelve patients were included. Three patients received 200 mg/day, 6 received 400 mg/day, and 3 received 800 mg/day; PTVs ranged from 105 to 500 cc. No dose-limiting toxicities occurred. The most common grade 2 toxicities were fatigue, neutropenia, nausea, and raised serum transaminases. Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy. There were no treatment-related deaths.

Conclusion: The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma. A dose of 800 mg/day is recommended for phase II evaluation.

Trial registration: EudraCT 2007-003211-31 ClinicalTrials.gov 00789763.

Trial registration: ClinicalTrials.gov NCT00789763.

Conflict of interest statement

Competing Interests: Bayer funded this study. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flowchart of the study.

Positron emission tomography-Computed tomography images show pathological uptake (SUVmax = 9.44) in a 4-cm pancreatic mass at baseline (A). There is no evidence of metabolic activity in the follow-up study (B), being considered as a complete response by EORTC criteria (PERCIST criteria).

Figure 2. Positron emission tomography-Computed tomography images show pathological uptake (SUVmax = 4.59) in a 20×38 mm mass in the pancreatic body at baseline (A).

There is no evidence of metabolic activity in the follow-up study (B), considered a complete response by EORTC criteria (PERCIST criteria).